Transfusion Independence Research Articles

Roxadustat versus placebo for patients with lower-risk myelodysplastic syndrome: MATTERHORN phase 3, double-blind, randomized controlled trial.

In patients with lower-risk myelodysplastic syndromes/neoplasms (MDS), response to first-line therapy is limited and transient. The MATTERHORN randomized, double-blind, phase 3 trial evaluated roxadustat versus placebo for patients with transfusion-dependent, lower-risk MDS. Eligible patients had very low-, low-, or intermediate-risk MDS with or without prior erythropoiesis-stimulating agent treatment, and a transfusion burden of 1-4 packed red blood cell (pRBC) units every 8 weeks (Q8W). Patients were randomized (3:2) to oral roxadustat (2.5 mg/kg) or placebo, both three times weekly, with best supportive care. Primary efficacy endpoint was transfusion independence (TI) for ≥56 days within 28 weeks (TI responders). MATTERHORN was terminated due to interim analysis outcomes not meeting statistical significance. In total, 272 patients were screened, and 140 patients were enrolled (82, roxadustat, and 58, placebo). At final analysis, 38/80 (47.5%) patients and 19/57 (33.3%) in the roxadustat and placebo arms, respectively, were TI responders (p = .217). A greater percentage of patients in the roxadustat arm with a transfusion burden of ≥2 pRBC units Q4W were TI responders (36.1%; 13/36) compared with the placebo arm (11.5%; 3/26; p-nominal = .047). The seven on-study deaths (4, roxadustat, and 3, placebo) were considered unrelated to treatment. Three roxadustat patients progressed to acute myeloid leukemia. Despite MATTERHORN not meeting its primary endpoint, a numerically higher TI rate was achieved with roxadustat treatment compared with placebo. Further analyses are needed to confirm the MDS patient subgroups deriving clinical benefit from this novel treatment.

Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis

AbstractThe ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non–transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); and patients in cohort 3A/3B had stable ruxolitinib treatment before and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary end point was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary end point. In cohorts 1 and 3A (NTD), 27% and 50% of patients, respectively, had mean hemoglobin increase of ≥1.5 g/dL from baseline. Among TD patients, ∼50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. This trial was registered at www.ClinicalTrials.gov as #NCT03194542.

Patient (pt) experience with and perceptions of transfusion-dependent (TD) and transfusion-independent (TI) myelofibrosis (MF): A qualitative interview study.

e23110 Background: MF is a rare myeloproliferative neoplasm for which Janus kinase inhibitors are the standard of care. Some Janus kinase inhibitors can exacerbate anemia, a hallmark feature of MF that increases in severity with disease progression. Red blood cell transfusions are an important component of anemia management, but transfusion dependence is an independent predictor of poor survival outcomes and is inversely correlated with quality of life (QOL). The current study aimed to elicit the perceived direct and indirect burden of transfusion dependence and its impact on pts with MF. Methods: Concept elicitation interviews were conducted remotely with Janus kinase inhibitor–experienced and symptomatic (MF Symptom Assessment Form v4.0 Total Symptom Score [TSS] ≥10) pts with MF across the US, UK, Germany, Italy, Spain, and Poland (N = 20). Five TD pts (≥2 blood transfusions in any 1 mo over the last 3 mo) and 15 TI pts (≤1 blood transfusion in any 1 mo over the last 3 mo) participated in 60-minute interviews, which followed a semistructured guide including open-ended questions and completion of ranking exercises and sociodemographic and clinical forms. Results: Of 20 pts, mean age was 59 years, 50% were male, and85% received a diagnosis of anemia after their MF diagnosis. Pts with anemia experienced a range of related symptoms, including fatigue (94%), weakness (53%), and night sweats (29%). These symptoms impacted several QOL domains, including emotional (88%) and physical (71%) health and social life (71%). Most pts (18 of 20) had received a transfusion in the past, of whom 5 were TD. In addition to higher transfusion burden, TD pts had higher symptom burden than TI pts (mean TSS, 30.8 vs 27.9).TD pts endorsed challenges with frequent transfusions relating to clinical concerns/safety (100%), convenience (100%), and travel (80%), all of which remained concerns when thinking about being TD in the future (40% each). These challenges resulted in emotional (80%) and physical (60%) impacts and impacts to activities of daily living (60%). Four of 5 (80%) reported that going ≥12 weeks without a transfusion would be helpful and positively impact their QOL. Similarly, TI pts felt it was important to remain TI, with 73% expressing concerns about becoming TD in the future. Regarding the most important MF treatment outcomes, MF symptom reduction and overall survival were the most common (40% each) among TD pts, and reduction/avoidance of transfusion was the most common (40%) among TI pts. Conclusions: These interviews characterize the substantial negative experiences with and perceptions of anemia and transfusions in pts with MF who are TD and those who are TI but concerned about becoming TD in the future. These findings highlight the value of treatment options that reduce/eliminate transfusion burden and prevent future transfusions in improving the experiences of pts with MF.

A call for improved anemia treatments in myelofibrosis: A single-center retrospective study.

e18531 Background: Anemia in myelofibrosis (MF) is associated with poor prognosis and decreased quality of life. Effective treatments are limited, posing a significant challenge in clinical management. This study aims to provide insights into the treatment of anemia in MF patients from an underserved urban tertiary care center. Methods: We retrospectively reviewed 88 MF patients referred to our center in the Bronx, NY between 2000 and 2023. Demographic data, presence of anemia (hemoglobin ≦10 g/dl) at time of diagnosis or referral (TODR), transfusion dependence ( ≥ 2 units on ≥2 occasions within 8 weeks), anemia treatments, disease modifying treatment, and anemia response to treatments (as defined by the IWG-MRT and ELN consensus report) were assessed via non-parametric tests and univariate cox regression. Events were defined as death from any cause or development of anemia. Patients with missing data were excluded. Results: Among 88 patients analyzed, 77 (87.5%) experienced anemia during the study period. Overall survival (OS) for anemic patients was 7.7 years with 31 deaths, versus only 1 death in the non-anemic group. 51 (60%) of patients were anemic at TODR. For patients not anemic at TODR, median time to anemia (TTA) was 31 months. Patients with HMR (n=24) had faster median TTA than those without (22 vs. 49 months, p = 0.1). All triple-negative (TN) patients (n=8) were anemic at TODR and had statistically lower initial hemoglobin compared to patients with driver mutations (7.4 g/dl vs. 9.9 g/dl, p = 0.0023). Among anemic patients (n=77), age > 65 was associated with poorer OS (HR 2.293, CI 1.076 - 4.887, p=.0315), while transfusion dependency (HR 2.093, CI 0.4777 - 0.9422, p=0.0697) and Ruxolitinib use (HR 2.843, CI 0.9912 - 8.155, HR 0.052) approached significance. Secondary anemia treatments did not impact OS (HR 0.9346, CI 0.4537 - 1.925, p=.854) and are summarized in the table. Most patients received Ruxolitinib (68.8%) and hydroxyurea (35.06%), while fewer received Momelotinib (N = 4), Pacritinib (N = 6), or Fedratinib (N = 4). Conclusions: Our findings highlight the limited effectiveness of current treatments in reducing transfusion burden and anemia in MF, and that patients of higher genetic risk may be more susceptible to developing anemia. Transfusion dependency and treatment non-response are marginally associated with poorer outcomes, emphasizing the need for newer therapies. [Table: see text]

Clinical benefit of luspatercept treatment (tx) in transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)–naive patients (pts) with very low-, low- or intermediate-risk myelodysplastic syndromes (MDS) in the COMMANDS trial.

6565 Background: There is an unmet need for effective tx that provides durable benefit for pts with anemia due to lower-risk MDS (LR-MDS). Here we report clinically meaningful responses to luspatercept tx in TD, ESA-naive pts with LR-MDS in the COMMANDS trial. Methods: Eligible pts were ≥ 18 years of age, had LR-MDS with or without ring sideroblasts and < 5% bone marrow blasts, endogenous serum erythropoietin < 500 U/L, required red blood cell (RBC) transfusions (defined as 2−6 RBC units/8 weeks [wk] for ≥ 8 wk prior to randomization), and were ESA-naive. Pts were randomized 1:1 to subcutaneous administration of luspatercept (1.0–1.75 mg/kg) once every 3 wk or epoetin alfa (EA; 450–1050 IU/kg) once weekly for ≥ 24 wk. New assessments of clinical benefit reported here include achievement and duration of ≥ 50% reduction in RBC units transfused over ≥ 12 wk (wk 1–end of tx [EOT]), transfusion burden (TB) on tx (wk 1–24), time to first transfusion, achievement and cumulative duration of all separate RBC transfusion independence (RBC-TI) ≥ 12 wk response episodes, and mean hemoglobin (Hb) increase ≥ 1.5 g/dL over wk 1–24. Results: As of March 31, 2023, 151/182 (83.0%) luspatercept- and 121/181 (66.9%) EA-treated pts achieved ≥ 50% reduction in RBC units transfused over ≥ 12 wk (wk 1–EOT; P= 0.0002), with median (95% confidence interval [CI]) durations of 130.0 (120.6–not evaluable [NE]) and 77.0 (54.9–123.1) wk, respectively ( P = 0.0004). A greater proportion of luspatercept vs EA pts achieved ≥ 50% reduction in RBC units transfused over ≥ 12 wk (wk 1–EOT), regardless of baseline (BL) TB: 105/118 (89.0%) luspatercept vs 82/111 (73.9%) EA pts with BL TB < 4 RBC units/8 wk and 46/64 (71.9%) luspatercept vs 39/70 (55.7%) EA pts with TB ≥ 4 RBC units/8 wk. The median (interquartile range) number of RBC units transfused during wk 1–24 of tx was 1.0 (0–5.0) in the luspatercept arm and 3.0 (0–8.0) in the EA arm. The median (95% CI) time to first transfusion was 155.0 (80.0–266.0) days for luspatercept vs 42.0 (23.0–55.0) days for EA pts ( P < 0.0001). Among pts who achieved RBC-TI ≥ 12 wk (wk 1–24), 22/124 (17.7%) luspatercept pts vs 12/88 (13.6%) EA pts achieved ≥ 2 separate RBC-TI ≥ 12 wk response episodes and cumulative median (95% CI) duration of all response episodes was 147.9 (122.0–NE) wk in the luspatercept arm and 95.1 (73.1–NE) wk in the EA arm ( P = 0.0067). Mean Hb increase ≥ 1.5 g/dL over wk 1–24 was achieved by 135/182 (74.2%) luspatercept pts and 95/181 (52.5%) EA pts ( P < 0.0001). Conclusions: Significantly greater proportions of luspatercept vs EA pts achieved improvements in Hb levels, reduction in TB and RBC units transfused, and had durable RBC-TI responses. Luspatercept provided clinically meaningful outcomes, supporting its use as the preferred tx for ESA-naive pts with LR-MDS-associated anemia. Clinical trial information: NCT03682536 .

Efficacy of imetelstat on red blood cell (RBC)-transfusion independence (TI) in the absence of platelet transfusions or myeloid growth factors in IMerge.

6566 Background: In the IMerge trial (NCT02598661) of RBC transfusion-dependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory to or ineligible for erythropoiesis stimulating agents, imetelstat showed significant efficacy vs placebo (PBO) for 8-wk, 24-wk, and 1-y TI endpoints, with neutropenia and thrombocytopenia as the most common adverse events (Platzbecker. Lancet 2024). Supportive care was given to all pts as needed, per investigator discretion. Here we report RBC-TI rates in the absence of platelet transfusions or myeloid growth factor use. Separately, RBC-TI with mean central hemoglobin (Hb) rise of ≥1.5 g/d was assessed in all pts. Methods: Pts were randomized 2:1 to receive imetelstat (n=118) 7.5 mg/kg or PBO (n=60) Q4W IV until disease progression. Primary endpoint was 8-wk RBC-TI; 24-wk RBC-TI was a key secondary endpoint. Primary analysis cutoff was Oct 2022, with Oct 2023 cutoff for 1-y RBC-TI analyses. Results: Overall, 21/118 (18%) pts in the imetelstat group and 1/60 (2%) pts in the PBO group needed platelet transfusions; 41/118 (35%) and 2/60 (3%) pts received myeloid growth factors, respectively. Significantly higher percentages of pts achieved 8-wk, 24-wk, and 1-y RBC-TI with imetelstat vs PBO in the absence of either platelet transfusions or growth factor support (Table). In a separate analysis, 8-wk, 24-wk, and 1-y RBC-TI and concurrent Hb rise of ≥1.5 g/dL with imetelstat vs PBO occurred in 28% vs 2%, 23% vs 0%, and 17% vs 0% of pts, respectively (Table). Among responders, imetelstat increased median central Hb levels compared with PBO: 3.6 g/dL vs 0.8 g/dL for 8-wk, 4.2 g/dL vs 1.1 g/dL for 24-wk, and 5.2 g/dL vs 1.7 g/dL for 1-y RBC-TI. Conclusions: Results from this subanalysis confirm that pts who achieve RBC-TI with imetelstat do so without developing severe neutropenia and thrombocytopenia (functionally defined as needing myeloid growth factors or platelet transfusions, respectively), therefore not negating the clinical benefit of the drug. Imetelstat also led to significant rise in Hb levels in RBC-TI responders, particularly long-term responders. These data further support the efficacy of imetelstat in TD pts with LR-MDS. Clinical trial information: NCT02598661 . [Table: see text]

Olutasidenib for mutated IDH1 acute myeloid leukemia: Final five-year results from the phase 2 pivotal cohort.

6528 Background: Olutasidenib is a potent, selective, oral inhibitor of mIDH1 and is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, Phase 2, open-label, multicenter trial (NCT02719574). We report final five-year results from the pivotal cohort. Methods: In the pivotal cohort of the Phase 2 trial, patients with mIDH1 AML received olutasidenib 150mg BID. Primary endpoint was complete remission (CR) + CR with partial hematologic recovery (CRh) by modified IWG Criteria 2003. Data cutoff: May 15, 2023. Results: Baseline characteristics of 153 enrolled patients are shown in Table. Of 147 efficacy evaluable patients, CR was achieved in 32% (95% CI: 24.5, 40.2) and CR/CRh in 35% (95% CI: 27, 43; P<0.0001). Median time to CR/CRh was 1.9 mo (range: 0.9, 5.6). The median duration of CR/CRh was 25.3 mo (95% CI: 13.5, not reached), with maximum duration 54.6 mo. Overall response rate was 48% (95% CI: 40, 56.7), with median duration 15.5 mo (95% CI: 7.4, 26.2) and maximum duration 54.6 mo. Median overall survival was 11.6 mo (95%CI: 8.9, 15.5). In the 12 patients R/R to prior venetoclax, 33% achieved a CR/CRh; median duration of CR/CRh is not reached (ongoing at 54.3 months), and median overall survival is 16.2 months (95%CI: 2.6, not reached). Transfusion independence from red blood cells and platelets was achieved in 34 of 87 (39%) patients and 28 of 69 (41%) patients, respectively, who were dependent at baseline. 16 (11%) patients proceeded to stem cell transplant. The 5-year safety profile was consistent with what was previously reported. The most common AEs (% reported over 3 years and over the full 5 years) were: febrile neutropenia (22% and 22%), constipation (26% and 27%), diarrhea (20% and 21%), nausea (38% and 39%), fatigue (23% and 23%), pyrexia (24% and 24%), hypokalaemia (20% and 22%), red blood cell count decreased (26% and 26%), white blood cell count increased (25% and 25%). Differentiation syndrome was reported in 14% by Year 3, with no new events by Year 5. The safety profile was stable with long-term follow up. Conclusions: This analysis provides an additional 2 years of data beyond the results that led to FDA approval of olutasidenib. This first report of the five-year data further demonstrates the rapid and durable responses observed with olutasidenib in heavily pretreated patients with mIDH1 AML, including those R/R to prior venetoclax. Clinical trial information: NCT02719574 . [Table: see text]

A prospective study of all-trans retinoic acid plus venetoclax and azacitidine in newly diagnosed acute myeloid leukemia.

6545 Background: Over the decade, anthracycline and cytarabine-based intensive chemotherapy remains the standard of care for acute myeloid leukemia (AML) but is hampered by serious toxicities like myelosuppression, increased transfusion requirement and disappointing clinical outcomes among the so-called poor-prognosis AML subsets. BCL-2 inhibitor plus azacitidine (AZA) has become a preferred treatment for AML, but the remission rate and overall survival (OS) are suboptimal. Apart from hematologic toxicities, 70.0% of patients were RBC transfusion dependent and 58.6% were platelet transfusion dependent. At present, all-trans retinoic acid (ATRA) is used as a differentiation drug, and there is no combination regimen with BCL-2 inhibitor. This study aimed to assess the efficacy and safety of ATRA plus venetoclax and AZA for newly diagnosed AML. Methods: This study enrolled 35 patients (≥18 years) with newly diagnosed AML between 2022 and 2023. For induction, patients received AZA (75 mg/m²) from Day 1 to 7, venetoclax at a target dose of 400 mg/d from Day 2 to 10, and ATRA (45 mg/m²/d) from Day 12 to 28 of each 28-day cycle for up to 2 cycles or until disease progression. Patients who achieved complete remission (CR) after two cycles of induction therapy received bone marrow transplantation or consolidation at their own discretion. For consolidation, patients received ATRA (45 mg/m²/d) from Day 1 to 21 and AZA (75 mg/m²) from Day 1 to 7 of each 28-day cycle for up to 4 cycles or until disease progression. For maintenance, patients received ATRA (45 mg/m²/d) for 21 days per cycle plus AZA (75 mg/m²). Maintenance therapy was given every 3 months until disease progression and ATRA was provided during intermissions. The primary endpoint was the composite CR rate (CR and CR with incomplete hematologic recovery) at the end of cycle 1 of inductive therapy. Results: As of now, the composite CR rate reached 74% (26/35) and the objective response rate reached 91% (32/35). The composite CR was 73% (11/15) in the adverse risk group and 75% (15/20) in the favorable-intermediate risk group at the end of cycle 1. Thirty-three patients entered cycle 2. The cumulative composite CR rate reached 91%(30/33) after 2 cycles of induction therapy. The median event-free survival was 390 days, and the median OS was 573 days. Platelet transfusion independence occurred in 17% (6/35) patients in cycle 1 and 73% (24/33) in cycle 2. Furthermore, 20% (7/35) and 73% (24/33) patients were RBC transfusion independent in cycle 1 and 2, respectively. Any-grade infections occurred in 74% (26/35) patients, including 12 before admission. Conclusions: The treatment regimen achieved a high composite CR rate and was well tolerated, with reduced hematologic toxicities in cycle 2 of induction therapy. Both adverse risk and favorable-intermediate risk patients benefited from the regimen, which holds promise for treating AML in adult patients. Clinical trial information: NCT05654194 .

A rare hemoglobinopathy duo: Hb Adana×Hb SEA in a 1-year-old patient – a case report and a brief literature review

Introduction and importance: Alpha thalassemia, resulting from nondeletional mutations, typically presents a more severe clinical manifestation compared to deletional mutations. Severe outcomes, such as hydrops fetalis, are associated with two specific nondeletional mutations. Therefore, DNA-based investigation is crucial for suspected carriers exhibiting subtle hematological abnormalities to facilitate proper diagnosis and effective family counseling. Case presentation: In this report, the authors describe a phenotypically normal 1-year-old girl with a rare and unique alpha-thalassemia genotype due to the presence of Hb Adana, a nondeletional alpha-chain mutation compounded with Hb SEA, an alpha-globin gene deletion. Clinical discussion: Mutations determine the clinical manifestations of alpha-thalassemia. DNA testing is recommended for suspected carriers with relatively small hematological abnormalities, for precise diagnosis and family counseling. To provide clinicians with a reference for diagnostic assessment, the authors established a genotype-phenotype correlations based on reported cases of Hb Adana following an exhaustive literature review. Being interested in determining which ethnicities and genotypes are associated with a higher risk of complications, including hydrops fetalis and transfusion dependence, the authors formalized a diagnostic evaluation guide and a guide for early screening to improve outcomes. Conclusion: Precise genetic evaluation is important for the diagnosis of alpha thalassemia. Hematologists play a critical role in managing these disorders, understanding genotype-phenotype correlations, and highlighting the significance of genetic counseling for high-risk patients. Extensive studies on these various genophenotypes are required to improve the diagnosis and prognosis of such medical conditions and advocate preventative strategies.

Association between ferritin, hemoglobin, and anemia response in jaktinib-treated patients with myelofibrosis: A post-hoc analysis of the ZGJAK006 study.

e18527 Background: Iron metabolism is disrupted in MF through the increased production of hepcidin, contributing to increased ferritin levels and iron-binding capacity, decreased serum iron levels and hemoglobin levels. Hepcidin production is upregulated by JAK/STAT pathway and BMP6/ACVR1/SMAD pathway. Jaktinib showed inhibition effects on JAK family and ACVR1 in preclinical studies. Anemia benefits with jaktinib treatment were observed in several clinical studies in MF pts. To explore the underlying mechanisms, we conducted a post-hoc analysis to investigate the change of ferritin levels during jaktinib treatment in MF pts with and without anemia response from a phase 2 study in pts who were intolerant to ruxolitinib (the ZGJAK006 study). Methods: Pts from the ZGJAK006 study were included if they were RBC transfusion dependent or with hemoglobin level ≤100 g/L at baseline. Transfusion dependence was assigned to pts with an average RBC transfusion of ≥2 U/month within 3 months prior to study drug administration. Pts without baseline ferritin results were excluded. Eligible pts were divided into 2 groups: anemia responders by week 24 and non-responders by week 24. Anemia response was defined as becoming RBC transfusion independent (defined by no transfusion in ≥12 consecutive weeks and hemoglobin ≥85 g/L) for transfusion-dependent pts or a ≥20 g/L increase in hemoglobin for non-transfusion-dependent pts with baseline hemoglobin ≤100 g/L. Results: A total of 39 pts were included in this post-hoc analysis, with 14 anemia responders and 25 non-responders. The baseline hemoglobin was similar in responders (median: 78.5 g/L) and non-responders (median: 78.0 g/L). The baseline levels of ferritin were higher than upper limit of normal in most pts (69.2%) with a median of 784.6 ng/mL in the overall population (697.5 ng/mL in responders and 785.0 ng/mL in non-responders). Ferritin decreased to 583.9 and 531.7 ng/mL at weeks 12 and 24, respectively. Notably, anemia responders had a fast reduction in ferritin and increase in hemoglobin compared to non-responders. In addition, the hemoglobin levels of those non-responders maintained were stable and eight non-responders had a ≥50% decrease in RBC infusion frequency or unit. Six (42.9%) of 14 responders and 10 (40.0%) of 25 non-responders achieved spleen volume reduction of ≥ 35% from baseline at week 24. Conclusions: In this post-hoc analysis of pts with anemic MF, jaktinib treatment led to improvement in iron metabolism and anemia. The results were in consistence with the known activities of jaktinib against JAK family and ACVR1. Moreover, similar spleen responses were observed for anemia responders and non-responders. Nevertheless, ferritin was the only marker of iron metabolism measured in this study, a translational biology study evaluating hepcidin may be needed to further support the clinical findings. Clinical trial information: NCT04217993 .

Momelotinib vs. ruxolitinib in myelofibrosis patient subgroups by baseline hemoglobin levels in the SIMPLIFY-1 trial

A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; N = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic). Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population. In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib. No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL.

Physical characteristics and factors affecting in pediatric thalassemia

Background: Thalassemia, one of the most common genetic diseases globally, can contribute to physical developmental delays in pediatric patients due to various factors. Chronic anemia, transfusional iron overload and chelation toxicity are key influences on the growth of children with thalassemia. Objective: This study aims to describe the physical development of pediatric thalassemia patients and assess the factors associated with their physical indices. Methods: A cross-sectional study involving 44 pediatric thalassemia patients receiving treatment at the Pediatric Center, Hue Central Hospital, was conducted from February 2023 to December 2023. Results: The study included 44 participants with an average age of 7.5 ± 4.3 years and an equal distribution of males and females. Of these, 64.5% were transfusion-dependent thalassemia patients. Serum ferritin levels exceeded 1000 ng/ml in 43.2% of participants, and the mean hemoglobin concentration was 67.4 ± 16.1 g/L. Of the evaluated children, 31.8% had height-for-age below -2SD, and 43.2% had weight-for-age below -2SD. Statistically significant associations were observed between height-for-age, weight-for-age, and both blood transfusion dependence and serum ferritin concentration (p &lt; 0.05). However, no significant differences were detected between physical indices and disease type or hemoglobin concentration (p &gt; 0.05). Conclusions: This study found that 31.8% of pediatric thalassemia patients experienced stunting, and 43.2% experienced wasting malnutrition. The degree of blood transfusion dependence and serum ferritin concentration were identified as factors associated with a higher prevalence of stunting and wasting malnutrition in children with thalassemia. Key words: Children, thalassemia, physical index, transfusion-dependent thalassemia, non-transfusion-dependent thalassemia.

Phase 1 Study of CK0801 in Treatment of Bone Marrow Failure Syndromes

BackgroundAn inflammatory bone marrow microenvironment contributes to acquired bone marrow failure syndromes. CK0801, an allogeneic T regulatory (Treg) cell therapy product, can potentially interrupt this continuous loop of inflammation and restore hematopoiesis.MethodsIn this phase 1 dose-escalation study of CK0801 Treg cells, we enrolled patients with bone marrow failure syndromes with suboptimal response to their prior therapy to determine the safety and efficacy of this treatment for bone marrow failure syndromes.ResultsWe enrolled nine patients with a median age of 57 years (range, 19 to 74) with an underlying diagnosis of aplastic anemia (n=4), myelofibrosis (n=4), or hypoplastic myelodysplasia (n=1). Patients had a median of three prior therapies for a bone marrow failure syndrome. Starting dose levels of CK0801 were 1 × 106 (n=3), 3 × 106 (n=3), and 10 × 106 (n=3) cells per kg of ideal body weight. No lymphodepletion was administered. CK0801 was administered in the outpatient setting with no infusion reactions, no grade 3 or 4 severe adverse reactions, and no dose-limiting toxicity. At 12 months, CK0801 induced objective responses in three of four patients with myelofibrosis (two had symptom response, one had anemia response, and one had stable disease) and three of four patients with aplastic anemia (three had partial response). Three of four transfusion-dependent patients at baseline achieved transfusion independence. Although the duration of observation was limited at 0.9 to 12 months, there were no observed increases in infections, no transformations to leukemia, and no deaths.ConclusionsIn previously treated patients, CK0801 demonstrated no dose-limiting toxicity and showed evidence of efficacy, providing proof of concept for targeting inflammation as a therapy for bone marrow failure. (Funded by Cellenkos Inc.; Clinicaltrials.gov number, NCT03773393.)

Safety and efficacy of narsoplimab in pediatric and adult patients with transplant-associated thrombotic microangiopathy: a real-world experience

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication following hematopoietic stem cell transplantation (HSCT). No approved treatments are currently available. This study presents real-world data obtained with narsoplimab, a human immunoglobulin G4 monoclonal antibody that inhibits MASP-2, the effector enzyme of the lectin pathway of the complement system. Between January 2018 and August 2023, 20 (13 adult and 7 pediatric) patients diagnosed with TA-TMA received narsoplimab under an ongoing compassionate use program. The diagnosis was based on internationally defined criteria for pediatric and adult patients. Fifteen patients fulfilled the criteria recently established by an international consensus on TA-TMA. Nineteen patients exhibited high-risk characteristics. Thirteen patients (65%) responded to narsoplimab, achieving transfusion independence and significant clinical improvement. The one-hundred-day Overall Survival (OS) post-TA-TMA diagnosis was 70%, and 100% for responders. Narsoplimab proved to be effective and safe in the treatment of high-risk TA-TMA, with no increased infectious complications or other safety signals of concern across all age groups. The high response rates and the encouraging survival outcomes underscore the potential of narsoplimab as a valuable therapeutic option, particularly for high-risk cases.

Modified lentiviral globin gene therapy for pediatric β0/β0 transfusion-dependent β-thalassemia: A single-center, single-arm pilot trial

β0/β0 thalassemia is the most severe type of transfusion-dependent β-thalassemia (TDT) and is still a challenge facing lentiviral gene therapy. Here, we report the interim analysis of a single-center, single-arm pilot trial (NCT05015920) evaluating the safety and efficacy of a β-globin expression-optimized and insulator-engineered lentivirus-modified cell product (BD211) in β0/β0 TDT. Two female children were enrolled, infused with BD211, and followed up for an average of 25.5months. Engraftment of genetically modified hematopoietic stem and progenitor cells was successful and sustained in both patients. No unexpected safety issues occurred during conditioning or after infusion. Both patients achieved transfusion independence for over 22months. The treatment extended the lifespan of red blood cells by over 42days. Single-cell DNA/RNA-sequencing analysis of the dynamic changes of gene-modified cells, transgene expression, and oncogene activation showed no notable adverse effects. Optimized lentiviral gene therapy may safely and effectively treat all β-thalassemia.

Complete remission with partial hematological recovery as a palliative endpoint for treatment of acute myeloid leukemia

AbstractComplete remission with partial hematological recovery (CRh) has been used as an efficacy endpoint in clinical trials of nonmyelosuppressive drugs for acute myeloid leukemia (AML). We conducted a pooled analysis to characterize the clinical outcomes for patients with AML who achieved CRh after treatment with ivosidenib, olutasidenib, enasidenib, or gilteritinib monotherapy in clinical trials used to support marketing applications. The study cohort included 841 adult patients treated at the recommended drug dosage; 64.6% were red blood cell or platelet transfusion dependent at study baseline. Correlations between disease response and outcomes were assessed by logistic regression modeling for categorical variables and by Cox proportional hazards modeling for time-to-event variables. Patients with CRh had a higher proportion with transfusion independence (TI) for at least 56 days (TI-56; 92.3% vs 22.3%; P < .0001) or TI for at least 112 days (TI-112; 63.5% vs 8.7%; P < .0001), a reduced risk over time for severe infection (hazard ratio [HR], 0.43; P = .0007) or severe bleeding (HR, 0.17; P = .01), and a longer overall survival (OS; HR, 0.31; P < .0001) than patients with no response. The effects were consistent across drugs. In comparison with patients with CR, the effect sizes for CRh were similar for TI-56 and for risk over time of infection or bleeding but less for TI-112 and OS. CRh is associated with clinical benefits consistent with clinically meaningful palliative effects for the treatment of AML with nonmyelosuppressive drugs, although less robustly than for CR.

The impact of infused red blood cell volume on major and bidirectional ABO-mismatched bone marrow transplantation

Background aimsABO incompatibility does not hinder bone marrow transplantation (BMT), but it has been associated with worse outcomes and additional adverse events. This study aimed to verify the impact of incompatible red blood cells (iRBCs) in allogeneic BMT and to determine a safe number of iRBCs to be infused. MethodsWe compared ABO-incompatible (iABO) allogeneic BMT (n = 42) with ABO-compatible allogeneic BMT (n = 44) and evaluated the impact of the number of infused iRBCs on outcomes and adverse events. ResultsThe iABO patients demonstrated delayed time to transfusion independence at 30 days and 60 days, increased requirement for red blood cell (RBC) transfusion and greater hemolysis signals and incidence of pure red cell aplasia. Neutrophil/platelet engraftment, length of hospitalization post-transplant, platelet units required, graft-versus-host disease occurrence and overall survival were similar in both groups. Patients in the iABO group received 1.03 × 1010 iRBCs/kg (range, 0.36–3.88). Infusion of iRBCs >1.0 × 1010 /kg was related to graft failure or death before neutrophil engraftment or platelet engraftment or both as well as increased plasma requirement and increased creatinine. Our results also suggest that antibody titers impact the transplantation scenario. ConclusionsThe iABO transplantation showed some unfavorable outcomes. It is important to monitor the value of iRBCs to be infused, considering the recipient antibody titers. We propose using the number of iRBCs (iRBCs/kg) as a dose parameter with regard to infused iRBCs. Further studies are necessary to clarify the maximum safe number of iRBCs in iABO transplants.

Prognostic impact of the conditioning intensity on outcomes after allogeneic transplantation for MDS with low blasts: a nationwide retrospective study by the adult MDS working group of the Japan Society for Transplantation and Cellular Therapy.

Poor prognostic factors, such as transfusion dependency and chromosomal risk, need to be considered in the indication of allogeneic hematopoietic cell transplantation (allo-HCT) for patients harboring myelodysplastic syndromes with less than 5% marrow blasts (MDS-Lo). We analyzed the post-transplant outcomes of 1229 MDS-Lo patients who received myeloablative (MAC)(n = 651), reduced-intensity (RIC)(n = 397), and non-myeloablative conditioning (NMAC) regimens (n = 181). The multivariate analysis revealed that the RIC group had better chronic graft-versus-host disease (GVHD)- and relapse-free survival (CRFS) (P = 0.021), and GVHD- and relapse-free survival (GRFS) than the MAC group (P = 0.001), while no significant differences were observed between the NMAC and MAC groups. In the subgroup analysis, the MAC group has better overall survival (P = 0.008) than the RIC group among patients with an HCT-comorbidity index (HCT-CI) score of 0, while the RIC group had better overall survival (P = 0.029) than the MAC group among those with an HCT-CI score ≥3. According to the type of conditioning regimen, total body irradiation 12 Gy-based MAC regimen showed better OS and CRFS than the other MAC regimen, and comparable outcomes to the RIC regimen. In conclusion, the RIC and NMAC regimens are promising options for MDS-Lo patients in addition to the MAC regimen.

A Systematic Literature Review of Predictors of Erythropoiesis-Stimulating Agent Failure in Lower-Risk Myelodysplastic Syndromes.

Erythropoiesis-stimulating agents (ESAs) are the first-line treatment option for anemia in patients with lower-risk myelodysplastic syndromes (LR-MDS). A systematic literature review was conducted to identify evidence of the association between prognostic factors and ESA response/failure in LR-MDS. MEDLINE, Embase, and relevant conferences were searched systematically for studies assessing the association between prognostic factors and ESA response/failure in adult patients. Of 1566 citations identified, 38 were included. Patient risk status in studies published from 2000 onwards was commonly assessed using the International Prognostic Scoring System (IPSS) or revised IPSS. ESA response was generally assessed using the International Working Group MDS criteria. Among the included studies, statistically significant relationships were found, in both univariate and multivariate analyses, between ESA response and the following prognostic factors: higher hemoglobin levels, lower serum erythropoietin levels, and transfusion independence. Furthermore, other prognostic factors such as age, bone marrow blasts, serum ferritin level, IPSS risk status, and karyotype status did not demonstrate statistically significant relationships with ESA response. This systematic literature review has confirmed prognostic factors of ESA response/failure. Guidance to correctly identify patients with these characteristics could be helpful for clinicians to provide optimal treatment.

Thalidomide and Hydroxyurea in Transfusion-Dependent Thalassemia: Efficacy, Safety Profile and Impact on Quality of Life

Transfusion-dependent thalassemia (TDT) is a major public health concern in India, requiring regular transfusions for survival. There is also significant morbidity caused by iron overload and transfusion related infections. Novel therapies targeting fetal hemoglobin induction are the need of the hour in resource-poor institutions for patients where transplant is not feasible for various reasons. This single arm, non-randomised prospective trial evaluated the efficacy and safety of a combination of low dose thalidomide and hydroxyurea in TDT along with the impact on quality of life (QoL). It included 41 TDT patients, who failed a reasonable trial of hydroxyurea. Complete response (CR) was defined as transfusion independence and partial response (PR) denoted at least a 50% reduction in transfusion requirement. The rest were defined as non-responders (NR). The mean age of the cohort was 20.78 years (range 12–45 years). There were 13 males and 28 females. Nineteen (46.3%), 7 (17.1%), and 15 (36.6%) patients achieved CR, PR, and no response respectively. The overall response rate (CR + PR) was 63.4%. There was a significant increase in hemoglobin levels with decrement in transfusion burden and ferritin levels. There were no significant adverse reactions. No significant predictors of response were found including amongst genetic modifiers. It improved the health related QoL amongst responders. The combination of thalidomide and hydroxyurea appear safe and effective in the reduction in transfusion requirement of TDT patients. The judicious use of these drugs can improve the quality of life and pave the way for patients not eligible for a stem cell transplant.